![]() 2Department of Reproductive Medicine, Chengdu Xinan Women’s Hospital, Chengdu, China.1Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.Moreover, p62 activates the mTOR signaling pathway, which results in tumor cell proliferation and growth regardless of growth factors levels, while p62 also promotes NF-kB activation, thus promoting inflammatory conditions, a cardinal feature of tumor growth.Shuang-Lan Chen 1 Chun-Meng Li 1 Wei Li 1 Qing-Song Liu 1 Shuang-Yuan Hu 1 Mao-Yuan Zhao 1 Dong-Sen Hu 2 Yan-Wei Hao 1 Jin-Hao Zeng 1,3* Yi Zhang 1* Downregulation of macroautophagy and subsequent accumulation of p62, results in activation of NRF-2, thus promoting a constant antioxidant response. Therefore, CMA seems to act as a potential compensatory mechanism to impaired macroautophagy. On the contrary, macroautophagy decreases subsequently, as established HCC liver tissue is characterized by accumulation of p62, a biomarker of macroautophagy activity. However, during the advanced stage of HCC development, CMA pathway is upregulated as a response to continuous stressful conditions and prolonged periods of nutrient deprivation that characterize tumor microenvironment. Nonetheless, during later stages of HCC development CMA seems to be upregulated under continuous severe stressful stimuli and when the tumor is established as a potential compensatory mechanism to impaired macroautophagy. The adverse conditions that characterize tumor microenvironment induce macroautophagy activity which acts as a tumor suppressor mechanism by promoting the degradation of dysfunctional cell components and by preventing inflammation and accumulation of p62 under stressful conditions. During the early stages of hepatocarcinogenesis macroautophagy is the first to sense energy deprivation. Under non-pathogenic conditions, both macroautophagy and CMA are activated at basal levels, while the central role of their autophagy flux is the degradation of dysfunctional cell components and the maintenance of liver homeostasis. Role of autophagy mechanism during hepatocarcinogenesis. The multimerization of LAMP-2A results in the sequestration of the autophagic cargo into the lysosomal lumen and the subsequent degradation. LAMP-2A is a receptor protein residing in the lysosomal membranes which interact with the HSC70-protein complex. This complex also contains other co-chaperones, thereby mediating the translocation to the lysosomal membrane. ( b) CMA is a particular type of autophagy, which involves the interaction of HSC70 with cytosolic proteins containing the KFERQ motif. Stage four consists of the fusion of the autophagosome with the lysosome leading to the degradation of the sequestered autophagic cargo through lysosomal hydrolases. Elongation includes the interaction between the ATG-12 conjugation system with the LC3-conjugation system by promoting the bending of the phagophore membrane and resulting in the formation of the autophagosome, which engulfs the autophagic cargo. Nucleation includes the interaction of the ULK1 complex with the Class III PI3K complex, promoting the formation of the phagophore. ( a) Macroautophagy consists of five main stages initiation consists of activating the ULK1 complex after inhibition of mTORC1. Molecular pathways of macroautophagy and chaperone-mediated autophagy (CMA). The present review provides an update on the role of autophagy pathways in the development of HCC and data on how the modulation of the autophagic pathway could contribute to the most effective management of HCC.Ĭhaperone-mediated autophagy chemoresistance hepatocellular carcinoma macroautophagy. Moreover, the autophagy pathway seems to have a complex role during the metastatic stage, while induction of autophagy has been implicated as a potential mechanism of chemoresistance of HCC cells. Nonetheless, chaperone-mediated autophagy has been elucidated as a tumor-promoting mechanism contributing to cancer cell survival. Mounting evidence suggests that upregulation of macroautophagy plays a crucial role during the early stages of carcinogenesis as a tumor suppressor mechanism however, it has been also implicated in later stages promoting survival of cancer cells. Recently, two main autophagic pathways have emerged to play critical roles during hepatic oncogenesis, macroautophagy and chaperone-mediated autophagy. Autophagy acts as a double-edged sword during this process. The current therapeutic options for HCC management, during the advanced stage, provide short-term survival ranging from 10-14 months. Hepatocarcinogenesis is a long process with a complex pathophysiology.
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